EM Nerd-An Addendum to the Case of the Tarnished Standard

In a previous post we discussed the use of IVC variation and the concept of fluid responsiveness. Despite a strong physiological basis, no studies examining the use of fluid responsiveness to guide resuscitative efforts in patients with septic shock have been shown to improve patient important outcomes. Shortly after this post was released, Critical Care Medicine published an article by Bednarczyk et al, which appeared to address this very gap in the literature.

The article, “Incorporating Dynamic Assessment of Fluid Responsiveness Into Goal-Directed Therapy: A Systematic Review and Meta-Analysis”, reviewed the literature to identify RCTs which compared a standard resuscitative strategy to one which used some form of assessment of dynamic fluid responsiveness (1). Two abstracters independently identified 13 unique trials enrolling 1,652 patients in total.

A dynamic fluid responsiveness strategy was associated with decreased mortality compared to standard care (RR, 0.59; 95% CI, 0.42–0.83; I 2 = 0%; n = 1,586), the absolute risk reduction in mortality was –2.9% (95% CI, –5.6% to –0.2%). There was also an associated increase in ICU free days observed in the patients in the fluid responsiveness strategy group.

Upon first glance this paper appears to be the very critical appraisal of fluid responsiveness which until now was absent from the literature. However, from a methodological standpoint it is less than ideal. The vast majority the trials included were small, with a significant degree of clinical heterogeneity.Criteria used for determining fluid responsiveness included assessment of SVV with threshold greater than 10–15% in nine trials, assessment of PPV with threshold greater than 10% in one trial. Data on mortality were available in 12 of 13 trials. Mortality was recorded at hospital discharge in seven trials, 28–30 days in an additional four trials, and 90 days in a single trial. The trials included in this analysis consisted of nine trials that enrolled patients undergoing high risk intra-abdominal surgery, three trials of cardiac surgery patients, and one trial of patients with septic shock. And so it is difficult to generalize these results to the diverse cohort encountered in the ED and ICU.

Despite our love of medical gadgetry, when it comes down to it, the tools we use to determine when to administer fluid are far less important than the processes of care that determine how we how we use them. Take for example the FACCT trial, published by the ARDSNet trial group in the NEJM in 2006 (2). These authors conducted a 2 by 2 factorial RCT, compared resuscitative strategies using either CVP or a pulmonary artery catheter (PAC) as well as the benefit of a conservative vs liberal fluid strategy. The authors found no benefit in the use of a PAC when compared to CVP, but rather a fluid restrictive approach was what improved outcomes. In a secondary analysis published in Critical Care Medicine, Semler et al examined the effects of the liberal vs conservative treatment strategies depending on initial fluid status (3). The authors hypothesized that patients with an elevated CVP on presentation who were randomized to the conservative strategy would undergo more aggressive diuresis and thus fare significantly better than their liberal counterparts.

On the contrary, the authors found that in patients with an initial CVP greater than 8 mm Hg, no difference in 60-day mortality existed between the two fluid strategies. However, in patients with a CVP less than 8 mm Hg, the conservative strategy group demonstrated an impressive decrease in 60-day mortality (17% vs 36%; p = 0.005).

When Semler et al attempted to parse out potential causes for this unexpected benefit, they found that, although patients with a CVP greater than 8 mmHg randomized to the conservative arm received a larger amount of furosemide than those in the liberal arm, the overall amount of fluid administered between the groups was similar. Conversely, in patients with an initial CVP less than 8, the total dose of furosemide differed little, while the total dose of IV fluids was significantly greater in the patients randomized to the liberal fluid strategy. The authors hypothesized that fluid administration, not diuretic use, influenced outcomes in critically ill mechanically ventilated patients.

Conclusions are limited by the secondary nature of this analysis, and validation is certainly warranted, but the CLASSIC trial published by Hjortrup et al in Intensive Care Medicine in 2016 supports these findings (4). The authors enrolled patients 18 years or older, who were admitted to the ICU for sepsis with signs of severe circulatory impairment, who had received at least 30 mL/kg ideal body weight (IBW) of fluid, and who had shock defined as “ongoing infusion of norepinephrine to maintain blood pressure”. Patients were randomized to either a fluid restrictive or fluid liberal strategy. Patients in the fluid restrictive strategy, were permitted to receive a 250-500 mL bolus of isotonic crystalloid only in cases of severe hypoperfusion, defined as either “a serum lactate of at least 4 mmol/L, a MAP below 50 mmHg in spite of the infusion of norepinephrine, mottling beyond the edge of the kneecap, or oliguria, defined as urinary output at most 0.1 mL/kg IBW in the last hour”.

The standard care group guided fluid administration using dynamic (e.g. stroke volume variation) or static (e.g. blood pressure, heart rate) hemodynamic variable(s) of the clinician’s choice. The effect of a fluid bolus was to be assessed by re-evaluation before a repeated fluid bolus or after 30 min at the latest.

Over a one-year period 153 patients were randomized, 76 patients were allocated to the fluid restriction group and 77 to the standard care group. The median fluid administration over the first 5 days in the ICU was 500mL vs 2000mL, in the restrictive and liberal groups respectively. Despite clearing their lactate more quickly and demonstrating a larger volume of urinary output in early stages of their ICU stay, patients randomized to the liberal group did noticeably worse.

Neither of these trials are methodologically robust enough to make definitive statements on the true efficacy of restrictive fluid strategies. While not conclusive, these findings suggest that the specific tool used to determine fluid administration is far less important than selecting a threshold that effectively limits the administration of fluid in the post-resuscitation period.

With that in mind, a major determinant in any trial examining hemodynamic goals to guide fluid administration is the control arm. Most of these trials in the Bednarczyk et al meta-analysis were performed in the perioperative period. How these findings are extrapolated to patients in septic shock is unclear.

In the only trial included in this meta-analysis that examined septic patients, the authors compared the use of a PICCO device to a strategy that determined the administration of fluid using CVP (5). The threshold to administer a 500 cc fluid bolus in the CVP arm was a CVP less than 8 mm Hg. This is very similar to the liberal strategy in the FACCT trial. Not surprisingly these patients received more fluid and did significantly worse than the patients in the PICCO guided arm. It is still unclear if the trial’s findings were truly in support of a fluid responsiveness strategy or in opposition to a fluid liberal one.

Over-resuscitation rarely occurs in the spectacular fashion of our early goal-directed yesteryear. Instead it transpires in a far more clandestine manner. In small aliquots, administered surreptitiously overtime. Each single bolus when examined in isolation appears harmless, but in aggregate, the resulting fluid balance can be as devastating. At best, theBednarczyk et al meta-analysis demonstrates a fluid responsiveness strategy may be superior to a liberal CVP based approach. It remains unclear what such strategies would add when utilized in a more fluid frugal system.